Genetic factors contribute to variability in the pharmacokinetics of drug metabolism. Nearly half of all drugs are metabolized by Cytochrome P450 3A4 (CYP3A4), a liver enzyme. Many drugs are designed to interact with CYP3A4, rather than other CYP enzymes thought to be polymorphic, having high inter-individual variability in function because of genetic differences. However, CYP3A4 function also varies widely among individuals.
Coding region CYP3A4 polymorphisms are rare and account for only a small portion of inter-person variability in CYP3A metabolism. Except for the promoter allele CYP3A4*1B with ambiguous effect on expression, common CYP3A4 regulatory polymorphisms were thought to be lacking. Recent studies have identified a relatively common regulatory polymorphism, designated CYP3A4*22 with robust effects on hepatic CYP3A4 expression.
CYP3A4*22 accounts for a portion of the observed variability and can be used to predict metabolizer status for drugs interacting with CYP3A4. Another CYP enzyme, namely CYP3A5, is also variably expressed in the liver. Because of the two proteins' similarity, many drugs interact with both, whereas a number of drugs are preferentially metabolized by one of either CYP3A4 or CYP3A5. Frequent deleterious mutations are known in CYP3A5, such as CYP3A5*3 and—with lower frequency—CYP3A5*7. There is a need for methods of predicting drug metabolism using CYP3A4*22 with CYP3A5 alleles *1, *3 and *7 as biomarkers for predicting overall CYP3A activity.
To predict in vivo CYP3A metabolizer status for specific drugs, a relative role of CYP3A4 versus CYP3A5 in the metabolism of each drug must be known. There is a need for tools and methods for predicting the metabolizer status of a patient and predicting the efficacy of a drug metabolized by CYP3A4 and CYP3A5 enzymatic processes.